1. Academic Validation
  2. Rosiglitazone-activated PPARγ induces neurotrophic factor-α1 transcription contributing to neuroprotection

Rosiglitazone-activated PPARγ induces neurotrophic factor-α1 transcription contributing to neuroprotection

  • J Neurochem. 2015 Aug;134(3):463-70. doi: 10.1111/jnc.13152.
Erwan Thouennon 1 Yong Cheng 1 Vida Falahatian 1 Niamh X Cawley 1 Yoke Peng Loh 1
Affiliations

Affiliation

  • 1 Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Abstract

Brain Peroxisome Proliferator-activated Receptor gamma (PPARγ), a member of the Nuclear Receptor Superfamily of ligand-dependent transcription factors, is involved in neuroprotection. It is activated by the drug rosiglitazone, which then can increase the pro-survival protein B-cell lymphoma 2 (Bcl-2), to mediate neuroprotection. However, the mechanism underlying this molecular cascade remains unknown. Here, we show that the neuroprotective protein neurotrophic factor-α1 (NF-α1), which also induces the expression of Bcl-2, has a promoter that contains PPARγ-binding sites that are activated by rosiglitazone. Treatment of Neuro2a cells and primary hippocampal neurons with rosiglitazone increased endogenous NF-α1 expression and prevented H2 O2 -induced cytotoxicity. Concomitant with the increase in NF-α1, Bcl-2 was also increased in these cells. When siRNA against NF-α1 was used, the induction of Bcl-2 by rosiglitazone was prevented, and the neuroprotective effect of rosiglitazone was reduced. These results demonstrate that rosiglitazone-activated PPARγ directly induces the transcription of NF-α1, contributing to neuroprotection in neurons. We proposed the following cascade for neuroprotection against oxidative stress by rosiglitazone: Rosiglitazone enters the neuron and binds to Peroxisome Proliferator-activated Receptor gamma (PPARγ) in the nucleus. The PPARγ-rosiglitazone complex binds to the neurotrophic factor-α1 (NF-α1) promoter and activates the transcription of NF-α1 mRNA which is then translated to the protein. NF-α1 is the secreted, binds to a cognate receptor and activates the extracellular signal-regulated kinases (ERK) pathway. This in turn enhances the expression of the pro-survival protein, B-cell lymphoma 2 (Bcl-2) and inhibition of Caspase 3 (Csp-3) to mediate neuroprotection under oxidative stress. Akt, protein kinase B (PKB).

Keywords

BCL-2; hippocampus; neuroprotection; neurotrophic factor-α1; rosiglitazone.

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